Watchdog Reports

Disjointed regulation

Heidi Clark is on hand to encourage her daughter Marisa, now 12, during riding lessons at Fox Creek Farm in Menomonee Falls. While the jaw implants Clark received in 2000 have proved durable over the past decade, during that time chronic pain has been a daily companion.

Pain, disfigurement mar record on jaw implants - and testing is still sketchy

Before implanting a third artificial jaw joint in Heidi Clark's head, doctors had to remove particles of plastic from the second failed joint that had broken apart and become embedded in muscle.

It was the latest of five surgeries Clark has endured that have reshaped her face, damaged nerves and added to the intense pain and depression that have marked what husband Kevin calls her "long road to hell."

Like more than 10 million Americans, Clark has a condition known as temporomandibular joint disorder, or TMJ - a group of ailments affecting the joint connecting the jaw to the head.

While the disorder is often manageable and temporary, Clark first went under the knife in 1988 to be implanted with an unproven jaw joint device that had been allowed on the market by the U.S. Food and Drug Administration.

Her repeating nightmare has been experienced by thousands of others.

Since 1999, the FDA approved four jaw joint replacement devices despite weak and incomplete research clouded by potential conflicts of interest, a Journal Sentinel investigation has found. What's more, the agency approved the devices even after a disastrous series of failures and recalls during the 1980s.

The Journal Sentinel's review of several thousand pages of testimony and other documents found that the FDA ignored warnings, patient testimony and its own staff recommendations to sidewith device companies whose research was conducted by doctors with a financial stake in the outcome.

"There were a million red flags," said Mark Patters, who served as an FDA advisory panel member for all four of the device hearings and who voted to approve three of them between 1999 and 2002. "You don't have to know the particulars to know the science wasn't there."

The Journal Sentinel found the products were approved even though clinical trials were fraught with problems, including:

• Just two oral surgeons implanted nearly all of the devices in two of the trials.

Independent researchers say such arrangements raise red flags because clinical trials should be done at a variety of centers to get a true picture of how well a device works. When a small number of doctors implant most devices, it doesn't reflect the real-world results of surgeons with less experience with the products.

• What's more, there were financial conflicts of interest in both of those clinical trials.

In one, both doctors worked as consultants to the manufacturer, and one of them invented the device and later got royalty payments.

In the other trial, one doctor worked as a consultant to the manufacturer, helped develop the device and later received stock in the company.

• Substantial numbers of patients dropped out of all the trials, and little long-term follow-up data was available - including one trial that had data on only 34 patients at the three-year mark.

Independent doctors say this casts doubt on the findings and indicates the results may have been biased and overstated the success.

In a written response to the Journal Sentinel, the FDA stood by its approval of the devices.

Throughout the approval process, the watchdog agency appeared to be looking out more for the makers of the devices than patients, the Journal Sentinel found. Despite serious concerns, FDA advisory panels unanimously voted to approve the products in three out of four cases. With the fourth device, the advisory panel voted against approval but a higher FDA authority approved it months later anyway.

Patters, a periodontist and an associate dean at the University of Tennessee College of Dentistry, said he and other advisory members often deferred to oral surgeons on the panels who argued in closed session that the devices were needed even if poorly tested.

Financial conflicts of interest tainted all of the studies, said Christian Stohler, dean of the University of Maryland Dental School.

"There is very little science behind them," said Stohler, who serves as an adviser to the TMJ Association, a national patient advocacy group based in Brookfield.

Some doctors justify implanting the devices by saying a common problem in the jaw is best fixed by putting in a permanent device.

While that may work with joints such as hips, it is not always true with TMJ disorder - a poorly understood condition that can be caused by any number of factors, said Stohler.

And unlike artificial hips and knees, which often go into older people, TMJ devices typically are implanted in people in their 20s, 30s and 40s who must live with the devices for decades.

There are a few instances in which the benefits of the devices outweigh the risks - such as patients with cancer, trauma or severe rheumatoid arthritis in the joint, Stohler said. But those cases make up less than 2% of the implants installed.

Estimates suggest that over the last 20 years more than 1,000 people a year have undergone TMJ implant surgery.

"These devices should not be used in the numbers they have been used in," he said.

Began in high school

In high school, Heidi Clark first began experiencing problems with her jaw locking.

A few years later, pain and popping in the joint sent Clark, now 47, of Colgate, to an oral surgeon. After a series of surgeries in the 1980s, her condition continued to worsen. This was before the FDA began requiring TMJ device companies to prove the safety and effectiveness of their products.

Between 1989 and 2000 she underwent a succession of radical surgeries to implant total joint replacement devices from three different companies. Her medical bills, paid mostly through insurance, totaled more than $500,000.

The joint on her right side, made by Vitek Inc. of Houston, failed in 1991, two years after it was implanted. That device eventually was taken off the market because its materials fragmented, causing the body to attack the foreign bodies and leading to bone degeneration, permanent hearing damage and chronic pain. In some cases, bone loss in the skull from the immune system reaction actually exposed the brain.

It was replaced in 1991 with a joint made by TMJ Implants of Golden, Colo. By 1999, that joint also had failed. Plastic material from the device broke into tiny pieces that embedded in muscle tissue.

"It was everywhere," said Doran Ryan, an oral surgeon who operated on Clark in Milwaukee in 2000.

It was only in 1998 that the FDA began regulating TMJ device makers more closely.

Ryan has removed failed Vitek and TMJ Implants devices from hundreds of patients over the years.

The faulty Vitek device on one side and TMJ Implants device on the other side were removed in 2000 and replaced with joints made by TMJ Concepts of Camarillo, Calif. So far, those joints have held up. That product was approved by the FDA in 1999.

However, Clark's pain has not subsided.

"I wake up in the morning and I feel worse until I get my medicine," she says. "Just touching it hurts so bad. I have headaches every day. I try to do things to keep my mind off it."

She takes four Vicodin a day.

It hurts to bite into food. It hurts to talk. It hurts to smile.

"I just do it," she said. "You have to smile. What is life otherwise?"

Over the last 20 years, more than 2,000 cases like Clark's have filled the files of the TMJ Association, the Brookfield organization.

One of the most appalling: A Pennsylvania woman, Margaret Rose Hutchison, underwent 60 surgeries, receiving five total joint replacement devices.

She died in 2003 at the age of 41.

Hutchison, of South Park, Pa., received her first implant at age 26, said her sister, Mary Ann Zirngibl. While the official cause of death was listed as heart-related, she had severe infections and a highly compromised immune system because of all the surgeries, Zirngibl said.

"The TMJ patients of this country deserve better," said Terrie Cowley, a patient herself and president and co-founder of the organization.

Often TMJ patients are left broke when they run out of insurance, Cowley said.

Virtually unregulated

Many patients were victims of TMJ implant efforts that began in the 1980s and quickly became fiascos. There was virtually no regulation of the devices because of a law that grandfathered in medical devices that were "substantially equivalent" to products on the market before 1976.

In 1998, the FDA began requiring manufacturers to prove their devices were "safe and effective."

U.S. Sen. Herb Kohl (D-Wis.), chairman of the Senate's Special Committee on Aging, and his staff have been investigating complaints about TMJ devices.

"These devices can have benefits for some patients, but seem to have a particularly troubled history of regulation, with many people living in pain as a result," Kohl said in a statement.

The FDA declined to allow any staff members to be interviewed for this story. Instead, it provided written responses to questions about the four TMJ devices that it approved since 1999.

"TMJ patients can experience persistent pain despite treatment that includes repeated surgeries - and some chronic pain TMJ patients have no additional treatment options," The FDA response said. "After considering the totality of available information, the Agency believed that the overall assessment of risks and benefits favored approval."

The FDA also said it insisted on a carefully worded label to educate patients and practitioners, and requested that data be collected on additional patients as a condition of approval.

Even doctors associated with companies that make the devices acknowledge major flaws in the research. But they contend that approval was warranted because some patients needed the artificial joints.

"It is not scientific, but it is, unfortunately, the facts as we deal with them," said Louis Mercuri, an Illinois oral surgeon who helped develop and test one of the joint replacement devices. "We had patients who had nothing."

Though pain doesn't always improve, the devices can improve function in many patients, he said.

Critics say some patients who never should have received an implant started on a downward spiral after they did.

"These products should not be on the market unless the companies can prove that more people benefit from them than are harmed," said Diana Zuckerman, president of the National Research Center for Women & Families. "They can't do that."

Glaring deficiencies in clinical trial data presented by the three companies to the FDA was noted throughout FDA advisory panel hearings conducted between 1999 and 2002, the Journal Sentinel found in its investigation:

TMJ Implants

In May 1999, TMJ Implants of Golden, Colo., went before an advisory panel seeking approval for one of its joint replacement devices.

Susan Runner, head of the FDA's dental devices branch, said there was inadequate patient data to analyze the effectiveness of the device beyond 18 months, according to a transcript of the advisory panel hearing.

She also said there were deficiencies in the company's fatigue and wear testing data.

Concerns were voiced about dozens of serious injuries associated with the company's devices.

"It is particularly of concern, I think, for a company that has been selling TMJ implants for more than 30 years, that they have yet to conduct a rigorous scientific test," panel member Patters said at the meeting.

Questions were raised about the acrylic material used in one of the products - material that later would break apart and have to be scraped out of the side of Heidi Clark's head.

Despite the concerns, the FDA approved both the TMJ Implants' partial and total joint-replacement devices.

In September, Crocker Ventures, an investment firm, bought the company out of bankruptcy and said it would continue producing the devices.

"TMJ Implants has proven to have the best implant products on the market and a solid position and reputation as a leader in the industry," Gary Crocker, president of the firm, said in a news release at the time.

Crocker Ventures did not answer questions for this story.

Biomet

In August 2002, Peter Quinn, a University of Pennsylvania oral surgeon, and Biomet, the company he was doing research for, appeared before an FDA advisory panel, seeking approval of their total joint replacement device.

There were several problems with the research.

Of the original 180 trial cases, 132 were conducted by Quinn and 40 by Douglas Sinn, a Texas oral surgeon.

When 96% of the surgeries in a clinical trial are done by two doctors, the success of the device can be overstated because it does not reflect real-world results that less experienced surgeons are likely to have, said Charles Rosen, orthopedic surgeon and president of the Association for Medical Ethics.

In addition, both doctors worked as consultants to the company, and Quinn was the developer of the device.

"It's two surgeons getting good results," Rosen said. "There is nothing to mitigate that conflict of interest."

Quinn told the Journal Sentinel he assigned his patent rights to the company years before the device was approved. It was only in the last year that he began getting royalty payments, he said.

He estimated he has received about $20,000 a year as a consultant since 2002. Before that, he said, he got no more than $25,000, and all of that he donated to his university.

Despite serious concerns about the study, the advisory panel unanimously recommended approval of the device to the FDA.

A few months later, the FDA found serious violations in the clinical trial records maintained by Sinn in Texas. Fourteen of Sinn's 41 patients had missed follow-up visits, breaking the study protocol. Forms for 14 patients left out information about adverse reactions and complications they had suffered.

The agency issued a warning letter yet approved the device anyway, despite having complete data on only 85 patients who had devices for three years, nearly all of whom got their devices from Quinn and Sinn.

There are people with pain and lost function whose joints are badly deteriorated, Quinn, senior vice president of the University of Pennsylvania Health System, said in an interview. "What do you want me to do with them? You can't say, 'Wait 15 years.'

"This is the best data we have," he said. "I sleep very well. I would put it in a family member."

In a written response to the Journal Sentinel, Biomet said that at three years, patient satisfaction with its device was 99%. It said it has been sending reports on its study, which now includes 288 patients, up from 224 at the time of approval, to the FDA every year since the device was approved.

In addition, the company said it requires surgeons to take a course before implanting its device.

The FDA panel "thoroughly vetted" issues such as patient follow-up and bias and unanimously voted to approve the device, which helps patients with few options, Biomet spokesman Bill Kolter said in the statement.

TMJ Concepts

When TMJ Concepts appeared before an FDA advisory panel in 1999 seeking approval for its artificial joint device, stories of pain and suffering by patients from earlier TMJ device disasters were read into the record.

"Since these implants, I am unable to work and have a constant fever," a woman said in her letter. "Now my joints are coming out through my skin."

Another woman said: "I developed a massive lump when my first implants were put in. When I called the surgeon, he blamed me for flying in an airplane and then abandoned me."

Still another woman said, "The implants hurt so bad I cry all of the time. My surgeon told me these implants work 97% of the time."

Research on the TMJ Concepts device was marred by the high number of patients, 35%, who dropped out of the study.

Ideally, a three-year trial of a medical device should have a dropout rate of less than 6%, independent doctors say. When patients don't return, it could be a sign of dissatisfaction with the surgery's results.

TMJ Concepts researchers had lost track of so many patients that they had to rely on a subset of 111 patients for whom there was more complete data. The analysis of success over three years was based on only 34 patients, 31% of those who got the device. In addition, all 111 patients remaining had their devices implanted by Mercuri, the Illinois oral surgeon, and just one other doctor.

At the time of the panel hearing in 1999, Mercuri, then a professor of surgery at Loyola University School of Medicine in Chicago, said he had received minimal consultant's fees from the company during the previous 10 years.

However, in an interview with the Journal Sentinel, he said he started getting a stipend from the company in 2000. He also acknowledged that in 2000 he was granted stock in the manufacturer in lieu of any patent interest he might have.

In an interview, Mercuri conceded that the science behind the device was weak, but the FDA decided that something was needed to help patients.

"The only thing I can say is, the FDA thought in the case of TMJ Concepts that they had satisfied the test for safety and effectiveness," he said.

The FDA approved the device in 1999. TMJ Concepts did not comment for this story.

Regulatory pattern

The Food and Drug Administration's handling of TMJ devices follows a familiar pattern of the agency siding with device makers, despite concerns raised about the science they present.

In August, the Journal Sentinel reported that in 2002, the FDA approved Medtronic's BMP-2, a powerful biological agent for use in back surgery, despite evidence that doctors in that clinical trial who had financial relationships with the company got substantially better results with the product than doctors who did not have conflicts of interest.

The agency redacted the financial disclosures of the doctors and declined to release them.

This article is part of an ongoing series about how money and conflicts of interest affect medicine and patient care. John Fauber reported this story in a joint project of the Journal Sentinel and MedPage Today. MedPage Today provides a clinical perspective for physicians on breaking medical news at www.medpagetoday.com.

About John Fauber

John Fauber is an investigative medical reporter who focuses on conflicts of interest in medicine and how drug and medical device companies and the FDA influence the practice of medicine. He has won more than two dozen national journalism awards.